The purpose of this project is to identify the determinants of type 2 diabetes, obesity, and other chronic diseases in the Pima Indians, and elucidate their natural history. Genetic and environmental risk factors for type 2 diabetes have been studied. The residents of the study area, approximately 5000 people, have participated in a longitudinal population study since 1965, allowing observations of the natural history of diabetes mellitus. Risk factors for obesity, hypertension, and nephropathy are also studied, along with the relationships of these diseases to diabetes and their effects on mortality rates. The genetics of diabetes is studied by means of family studies and relationships of genetic markers to disease. The roles of obesity, serum insulin concentrations, impaired glucose regulation, occupational and leisure-time physical activity and diabetes in relatives are assessed. Studies of the genetics of type 2 diabetes and obesity are described in project report # Z01 DK 69028 PECR. Behavioral risk factors contribute to the incidence of type 2 diabetes in this population; both a self-identification of Anglo (as opposed to Indian) dietary preference and self-reported physical inactivity predict diabetes. It was determined that Pima Indian children become overweight, relative to national standards, even before the age of 5 years. Low serum levels of adiponectin predicted diabetes, suggesting that this recently-discovered hormone produced in fat cells may mediate the effect of adiposity on the development of type 2 diabetes. A longitudinal analysis of serum rheumatoid factor indicated a decline during the last three decades that was primarily due to a cohort effect. This supports the hypothesis of early-life influences on rheumatoid arthritis.